Wistar-Furth rats (WF) do not develop hypertension when treated with salt and mineralocorticoids and therefore may be useful for investigating the mechanisms of mineralocorticoid action and hypertension. In the present studies, we determined vascular and renal responses of WF to mineralocorticoids. Control Wistar rats (W) developed deoxycorticosterone acetate (DOCA)-NaCl and dexamethasone hypertension, whereas WF rats developed dexamethasone hypertension only. Aldosterone treatment of vascular smooth muscle cells cultured from WF resulted in 82% less upregulation of angiotensin II radioligand binding, 50% less induction of angiotensin II AT1a receptor mRNA, and 76% less potentiation of angiotensin II-stimulated inositol phosphates than did aldosterone treatment of cells from W. Similarly, DOCA-NaCl potentiated angiotensin II- and phenylephrine-stimulated contractions in aortic rings from W but not from WF. Although DOCA-NaCl treatment affected hypokalemia to an equal degree in WF and W, increases in renal citrate synthase activity (a specific renal mineralocorticoid response) were greater in W than in WF. WF manifest a partial defect in mineralocorticoid responsiveness in vascular smooth muscle and, possibly, in the kidney.